SHIVKU containing the envelope of HIV-1 is a recently derived virus that causes AIDS and neurological disease in Rh macaques after severe depletion of CD4+ T cells. In previous studies, we used this virus to characterize the histological nature of the neuropathological changes and the nature of the altered systemic infection during and after withdrawal of anti-retroviral therapy. We also established that it causes a low-grade systemic infection after given as a challenge to vaccinated animals. In this application, in Aim 1, we will use the model to obtain more detailed information on the chronology of development of CNS disease in order to better understand the nature of virus-host responses associated with this complication. This information will be used as a backdrop for intervention strategies focused on the nature of the infection in the CNS of animals placed on drug therapy and in vaccinated animals. Questions that cannot be answered in humans can now be approached. In Aim 2 we will determine the effects of anti-retroviral therapy on the progress of infection in the CNS and on neuropathological processes already in progress. In Aim 3 we will determine whether live vaccine virus causes infection in the CNS. Although vaccination prevented AIDS, SHIVKU given as challenge still caused systemic infection, a result that can be expected in immunized humans exposed to HIV-1. As part of Aim 3 we will determine also whether this low-grade infection by SHIVKU also becomes established in the CNS. Do these viruses which cause persistent CNS infection mutate along divergent pathways from virus in lymph nodes? In Aim 4 we will extend in vitro findings that anti-IL-4 strategies causes reduction of virus replication in macaque macrophages. We will use gene therapy with antisense IL-4 DNA to treat SHIV encephalitis in Rh macaques in attempts to cause reduction in virus replication in brain macrophages and thus cure the encephalitis.